1. Field of the invention.
The two, previously disclosed cephalosporins of the present invention possess the usual attributes of such compounds and are particularly useful in the treatment of bacterial infections, especially by oral administration. This invention provides improved processes for their production, isolation and purification.
2. Description of the prior art
The literature on cephalosporins has been reviewed, for example, by E. P. Abraham, Pharmacol. Rev. 14, 473-500 (1962), by I. M. Rollo, Ann. Rev. Pharmacol. 6, 218-221 (1966), by E. P. Abraham, Quart. Rev. (London) 21, 231 (1967), by E. Van Heyningen, Advan. Drug Res., 4, 1-70 (1967), by G. T. Stewart, The Penicillin Group of Drugs, Elsevier Publishing Company, New York, New York (1965) at pages 185-192 and briefly in Annual Reports in Medicinal Chemistry, Academic Press, Inc. 111 Fifth Avenue, New York, New York, 10003, by L. C. Cheney on pages 96-97 (1967), by K. Gerzon and R. B. Morin on pages 90-93 (1968), by K. Gerzon on pages 78-80 (1969) and by L. H. Conover on pages 101-102 (1970). New cephalosporins are frequently reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy as illustrated by Sassiver et al., Antimicrobial Agents and Chemotherapy, , 1968, American Society for Microbiology, Bethesda, Maryland, pages 101-114 (1969) and by Nishida et al., ibid, 236-243 (1970). Two excellent recent reviews are The Cephalosporins Microbiological, Chemical and Pharmacological Properties and Use in Chemotherapy of Infection, L. Weinstein and K. Kaplan, Annals of Internal Medicine, 72, 729-739 (1970) and Structure Activity Relationships Among Semisynthetic Cephalosporins, M. L. Sassiver and A. Lewis, Advances in Applied Microbiology, edited by D. Perlman, 13, 163-236 (1970), Academic Press, New York.
The original syntheses of 7-[D-.alpha.-amino-.alpha.-(4-hydroxy- and 3-chloro-4-hydroxy-phenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid, which have the structure ##SPC1##
Wherein R is hydrogen or chloro were disclosed in U.S. Pat. Nos. 3,489,751 and 3,489,752, both issued Jan. 13, 1970 (corresponding to Farmdoc No. 36,496, Netherlands Pat. No. 68/12382; Canada Pat. Nos. 842,799 and 842,800 and U.K. Pat. No. 1,240,687).
There are numerous patents and publications dealing with the simpler, related compound containing no substituents in the benzene ring which is the well-known antibacterial agent cephalexin. For example, syntheses of cephalexin are disclosed in Lilly's U.S. Pat. Nos. 3,507,861; 3,671,449; Belgium Pat. No. 737,761 (Farmdoc No. 12,621R; France Pat. No. 2,016,284) and U.K. Pat. No. 1,174,335 (Farmdoc No. 28,654) and Glaxo's West Germany Pat. No. 2,063,268 (Farmdoc No. 46,839S); Glaxo's U.S. Pat. Nos. 3,634,416 and 3,676,437 and Osaka's Japanese Pat. No. 72/24714R (Farmdoc No. 47,321S); J. Med. Chem., 12, 310-313 (1969) and J. Org. Chem. 36(9), 1259-1267 (1971).
Various salts, hydrates and complexes of cephalexin and processes for isolating and purifying cephalexin are disclosed in some of the above and in Lilly's U.S. Pat. Nos. 3,502,663; 3,655,656; 3,531,481; 3,676,434 and Glaxo's Belgium Pat. No. 753,910 (Farmdoc No. 08214S) and Belgium Pat. No. 764,055 (Farmdoc No. 60,231S; Canada Pat. No. 881,195). See also Journal of Pharmaceutical Sciences, 59(12), 1809-1814 (1970).
Of this cephalexin art only U.S. Pat. Nos. 3,507,861; 3,671,449; 3,634,416 and U.K. Pat. No. 1,174,335 make any reference to substituents in cephalexin's benzene ring; such disclosure in these four references is completely general in nature and includes no physical constants, yields or the like. None of these general disclosures appear to contemplate any particular disubstitution in the benzene ring and certainly no such compound is named.